Abiological Self-Assembly

非生物自组装

• 批准号: 8180793
• 负责人: Peter J Stang
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8180793
• 关键词: Affinity; Antifreeze Proteins; Antineoplastic Agents; Binding; Biochemical; Biological; Biological Process; Cell surface; Chemical Agents; Chemistry; Cilengitide; Complement; Complex; Cyclophosphamide; Disease; Doxorubicin; Drug Delivery Systems; Endothelium; Enzymes; Fluorouracil; Future; Gene Expression Regulation; Goals; Grant; Heart; Human; In Vitro; Integrins; Investigation; Kinetics; Life; Ligands; Literature; Medical; Membrane; Metals; Methodology; Methods; Microtubules; Modeling; Nucleic Acids; Organism; Pharmaceutical Preparations; Phospholipids; Preparation; Prevention; Process; Production; Progress Reports; Property; Proteins; Publishing; Research; Research Personnel; Ribosomes; Shapes; Specificity; Structure; System; Thermodynamics; Transfection; antitumor agent; base; chemotherapy; chymotrypsin; design; improved; innovation; insight; molecular recognition; nanoscale; novel; novel strategies; protein folding; repaired; self assembly; small molecule; tool; tumor

DESCRIPTION (provided by applicant): The broad long term objectives of this research are: (1) to develop efficient, new methods for the preparation of complex nanoscale molecules with well-defined shapes and sizes, by rational design, using abiological self- assembly; (2) to provide insights and gain a better understanding of molecular recognition phenomena and self-assembly processes; (3) to develop abiological self-assembly as a platform for novel biomedical applications. [Our specific goals are to: (a) examine encapsulation and host-guest interactions of small drug- like organic molecules, as well as the encapsulation of three diverse, widely-used commercially-available cancer drugs (fluorouracil, cyclophosphamide, doxorubicin); (b) study protein and enzyme encapsulation by pre-designed self-assembled metallacages; (c) develop targeted drug delivery methodologies via self- assembled metallacages and the multivalent display of peptidic (and other) integrin antagonists.] We will use abiological, coordination-driven and our "directional bonding" approach to achieve these aims. This methodology allows for the rapid, pre-designed, (rational) self-assembly of nanoscale systems with well- defined shapes and sizes, due to metal d-orbital involvement that allows dative, metal-ligand bonds to be highly directional. Moreover, coordination kinetics can be modulated to engage in self-repair to achieve thermodynamic control of the desired, pre-designed super structures. Self-assembly is at the heart of countless biological processes that all living organisms, from the simplest to humans, depend upon. Protein folding, nucleic acid assembly and tertiary structures, ribosomes, phospholipid membranes and microtubules are but representative examples of self-assembly. Insights gained from the proposed abiological self-assembly studies will be applicable to a better and more complete understanding of the complex, not well-understood biological self-assembly processes. If the aims of this application are achieved, biomedical researchers will have new tools and entirely new approaches for the formation of large, nanoscale, complex molecules with unique properties that will complement and enhance classical covalent synthetic methods. As a consequence, in the long term, these approaches will facilitate the discovery and production of improved chemical agents and chemotherapy for the treatment and possible prevention of medical disorders. PUBLIC HEALTH RELEVANCE: If the aims of this application are achieved, biomedical researchers will have new tools and entirely new approaches for the formation of large, nanoscale, complex molecules with unique properties that will complement and enhance classical covalent synthetic methods. As a consequence, in the long term, these approaches will facilitate the discovery and production of improved chemical agents and chemotherapy for the treatment and possible prevention of medical disorders and in particular. Additionally, in the future, innovative transfection systems and possible gene-regulation may evolve from these discoveries.

描述（由申请人提供）：这项研究的广泛长期目标是：（1）使用合理的设计，开发具有具有明确定义的形状和尺寸的复杂纳米级分子的新方法，并使用实用设计； （2）提供见解并更好地了解分子识别现象和自组装过程； （3）发展物质自组装作为新型生物医学应用的平台。 [我们的具体目标是：（a）检查小药物（例如有机分子）的封装和宿主 - 阵阵相互作用，以及三种多种多样的，广泛使用的商业可用的癌症药物（氟尿嘧啶，环磷酰胺，阿霉素）的封装； （b）通过预设计的自组装金属质量研究蛋白质和酶封装； （c）通过自组装金属和肽（和其他）整联蛋白拮抗剂的多价显示来开发有针对性的药物递送方法。]我们将使用以生物学，协调驱动的和我们的“定向键”方法来实现这些目标。这种方法允许通过金属D轨道涉及金属D-轨道涉及，具有良好的形状和尺寸的纳米级系统的快速，预先设计的（合理的）自组装，该系统允许剂量，金属配体键具有高度方向性。此外，可以调节协调动力学以进行自我修复，以实现对所需的预设计的超级结构的热力学控制。自组装是无数生物学过程的核心，从最简单到人类，所有生物都依靠。蛋白质折叠，核酸组装和三级结构，核糖体，磷脂膜和微管是自组装的代表性例子。从提出的生物学自组装研究中获得的见解将适用于对复杂而不是精心理解的生物学自组装过程的更好，更完整的理解。如果实现了本应用的目的，生物医学研究人员将采用新的工具和全新的方法，用于形成具有独特特性的大型纳米级，复杂分子，可以补充和增强经典的共价合成方法。因此，从长远来看，这些方法将促进化学剂的发现和生产，以治疗和预防医学疾病的化学疗法。 公共卫生相关性：如果实现了本应用的目的，生物医学研究人员将采用新的工具和全新的方法来形成具有独特特性的大型，纳米级，复杂的分子，以补充并增强经典的共价合成方法。因此，从长远来看，这些方法将促进化学剂的发现和生产，以及化学疗法，以治疗和预防医学疾病，尤其是。此外，将来，创新的转染系统和可能的基因调节可能会从这些发现中发展。